Inhibition constants, inhibitor concentrations and the prediction of inhibitory drug drug interactions: pitfalls, progress and promise

Curr Drug Metab. 2006 Jan;7(1):1-14. doi: 10.2174/138920006774832541.


Strategies and standards for predicting the likelihood of pharmacokinetically significant inhibitory drug-drug interactions for drug development purposes which rely primarily on projected in vivo concentrations of cytochrome P450 (CYP) or transporter inhibitors, [I], and in vitro estimates of their inhibitory constants, K(i), were specified in several commentaries based upon a conference held by the European Federation of Pharmaceutical Sciences (EUFEPS) several years ago. Since then the application of those strategies and standards has met with varying degrees of success. Many of the vexing issues that were identified in the EUFEPS Conference Report remain, while other issues are systematically being resolved. This article briefly reviews the underlying strategy in the prediction of the significance of inhibitory DDIs using [I]/K(i) ratios; some of the difficulties or pitfalls associated with the predictive application of [I]/K(i) ratios; and some of the recent refinements of the general strategy.

Publication types

  • Review

MeSH terms

  • Animals
  • Carrier Proteins / antagonists & inhibitors*
  • Cytochrome P-450 Enzyme Inhibitors
  • Drug Interactions*
  • Enzyme Inhibitors / pharmacology
  • Hepatocytes / drug effects
  • Humans
  • Microsomes, Liver / drug effects
  • Pharmacokinetics*
  • Predictive Value of Tests


  • Carrier Proteins
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors